Alzheimer disease is a neurodegenerative disease having pathological features such as degeneration or loss of nerve cells, formation of senile plaques and neurofibrillary tangles. Alzheimer disease causes symptoms of dementia such as gradual loss of memory, recognition, thinking, judgment or the like, and it eventually leads to death. No effective method for treating or preventing this disease has hitherto been known.
The main protein constituting a senile plaque deposited in the brain is β-amyloid protein which is composed of from 39 to 43 amino acids. β-Amyloid protein exhibits cytotoxicity, which is presumed to induce Alzheimer disease (Science, 259, 514 (1993)). β-Amyloid protein secreted from cells is a polypeptide composed mainly of 40 or 42 amino acids and particularly, that composed of 42 amino acids is known to deposit in the brain quickly because of strong aggregation property and in addition, have strong cytotoxicity (Journal of Biological Chemistry, 270, 7013 (1995)). β-Amyloid protein is produced ubiquitously in vivo, but its function remains unknown.
β-Amyloid protein is produced by processing of a β-amyloid precursor protein (APP) which is a membrane protein. Mutation of an APP gene is observed from patients suffering from familial Alzheimer disease. An increase in the production or secretion amount of β-amyloid protein is known to occur in the cells having this mutated gene introduced therein. This suggests that a medicament inhibiting the production or secretion of β-amyloid protein is effective for the prevention or treatment of Alzheimer disease.
In the processing of APP, BACE (β-site APP Cleaving Enzyme) (Science, 286, 735 (1999)) or Asp1 (Molecular and Cellular Neuroscience, 16, 609 (2000)), each an aspartic protease, is reported as a β secretase for cleaving the N terminal of β-amyloid protein. It is suggested strongly that presenilin participates in C-terminal cleavage events by γ-secretase (Nature, 398, 513 (1999)). Inhibitors of the secretase have been reported (Journal of Medicinal Chemistry, 44, 2039 (2001)), but most of the inhibitors are peptide compounds.
In WO00/50391, SMITH, et al., disclose compounds having a sulfonamide skeleton and capable of controlling production of β-amyloid protein. In WO01/70677 (GB 026827) BELANGER, et al., disclose compounds having a bicycloalkylsulfonamide skeleton and inhibiting γ-secretase.
An object of the present invention is to provide compounds having a structure different from that of the above-described known compounds, having excellent inhibitory action against production or secretion of β-amyloid protein and having desirable properties as pharmaceuticals.